In order to assess the effects of specific genes on premalignant progression in vivo,we have generated a line of transgenic mice in which the tetracycline suppressible transactivator (tTA) is targeted to the epidermis with a keratin 5 promoter. Founders for a transgenic line with the reverse transactivator rTA in which transactivation is induced by tetracycline have also been made but they have not been tested for expression. The efficacy of the BK5/tTA transgenic as a transactivator has been demonstrated by crossing the K5/tTA lines with a transgenic line expressing a tetO/beta-galactosidase transgene. Both systemic and topical doxycycline can suppress expression of beta-galactosidase in the double transgenic mice. We have generated several tetO transgenics with different target genes including an oncogenic c-ras and a constiuitively active TGF-beta1 in order to regulate their expression at specific stages of carcinogenesis.